We have studied the chemical basis of drug binding defects in uremia and have chemically identified the binding inhibitor to be 2-hydroxybenzoylglycine. This inhibitor, when added to normal human serum in vitro, induces the binding defects similar to those observed in uremic serum in vitro. This proposal describes our plans to further investigate the role of 2-hydroxybenzoylglycine in the pathophysiology of the uremic state. The first phase of our work will concentrate on the mechanism by which 2-hydroxybenzoylglycine inhibits the binding of acidic drugs and its effects on the activity of pharmacological agents. When these studies are completed, the studies will be extended to elucidate the role of 2-hydroxybenzoylglycine as one of the so-called "uremic toxins". Since none of the previous putative "uremic toxins" has been shown to explain any specific abnormalities in uremia, it seems important to evaluate other potential effects of 2-hydroxybenzoylglycine. Initial studies will be undertaken in experimental animals (rats) to determine the tissue distribution and tissue binding sites of 2-hydroxybenzoylglycine. Subsequent studies will be developed to elucidate its possible role in producing "uremic" encephalopathy, neuropathy, seizure disorders, hemolytic anemia, lipid disorders, and other problems associated with chronic renal failure. Exogenous sources of 2-hydroxybenzoylglycine and its precursors are multiple. We plan to study the precise biochemical mechanisms involved in the genesis of 2-hydroxybenzoylglycine, possible methods of removal of the substance from uremic serum which could become clinically adaptable, and limit the biogenesis of the compound in uremic patients by control of dietary intake of foods containing 2-hydroxybenzoylglycine precursors. Further information gained from the study of 2-hydroxybenzoylglycine as a pathological agent will definitely aid in the correction of binding defects in uremic patients and other abnormalities which may be due to the accumulation of 2-hydroxybenzoylglycine.